The hypothesis to be tested is that conditions or substances which alter cerebral sterols during critical periods of brain development can result in onset of chronic epileptiform activity later in life. We demonstrated that onset of cobalt-induced epilepsy in the rat is preceded by major alterations in the concentration of cholesterol and cholesterol esters in brain. Treatment of the neonatal but not juvenile rat with U18666A, an inhibitor of cerebral cholesterol synthesis, results in the development of chronic epileptiform activity later in life. The observations with U18666A suggest the possibility that alteration of cerebral sterols for perhaps only short periods during times of active development and growth of the brain can eventually result in a chronic seizure state. To critically evaluate this possibility studies will be conducted to correlate brain levels of U18666A with inhibition of synthesis of brain sterols, to determine the distributions of 3H-labeled U18666A in brain and to determine whether other drugs similar to U18666A also produce epilepsy. The proposed project will attempt to correlate cerebral concentrations of U18666A with inhibition of brain sterol synthesis, measured in vitro and in vivo, following various periods of drug treatment. Studies will also be conducted to determine the effects of U18666A upon the patterns of sterol biosynthesis and upon the formation of other brain lipids. Radioautography of brain slices following injection of 3H-labeled U18666A offers the exciting possibility of identifying structures in brain where the drug could localize, and thus, might permit identification of specific tissue or cellular sites responsible for the 18666A induced epilepsy. In order to determine if production of epileptiform activity is a general consequence of altering brain sterols during critical periods, the ability of various cholesterol synthesis inhibitors, similar and dissimilar to U18666A, to produce a chronic seizure state will be evaluated. The drugs to be examined are triparanol, 20, 25-diazacholesterol, AY9944, zuclomiphene and clofibrate. If our theory is correct, we expect that drugs similar in action to U18666A can also produce a chronic epileptiform state.